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1.  In Vivo Assessment of Aqueous Humor Dynamics Upon Chronic Ocular Hypertension and Hypotensive Drug Treatment Using Gadolinium-Enhanced MRI 
Although glaucoma treatments alter aqueous humor (AH) dynamics to lower intraocular pressure, the regulatory mechanisms of AH circulation and their contributions to the pathogenesis of ocular hypertension and glaucoma remain unclear. We hypothesized that gadolinium-enhanced magnetic resonance imaging (Gd-MRI) can visualize and assess AH dynamics upon sustained intraocular pressure elevation and pharmacologic interventions.
Gadolinium contrast agent was systemically administered to adult rats to mimic soluble AH components entering the anterior chamber (AC) via blood–aqueous barrier. Dynamic Gd-MRI was applied to examine the signal enhancement in AC and vitreous body upon microbead-induced ocular hypertension and unilateral topical applications of latanoprost, timolol maleate, and brimonidine tartrate to healthy eyes.
Gadolinium signal time courses in microbead-induced hypertensive eyes possessed faster initial gadolinium uptake and higher peak signals in AC than control eyes, reflective of reduced gadolinium clearance upon microbead occlusion. Opposite trends were observed in latanoprost- and timolol-treated eyes, indicative of their respective drug actions on increased uveoscleral outflow and reduced AH production. The slowest initial gadolinium uptake but strongest peak signals were found in AC of both brimonidine-treated and untreated fellow eyes. These findings drew attention to the systemic effects of topical hypotensive drug treatment. Gadolinium leaked into the vitreous of microbead-induced hypertensive eyes and brimonidine-treated and untreated fellow eyes, suggestive of a compromise of aqueous–vitreous or blood–ocular barrier integrity.
Gadolinium-enhanced MRI allows spatiotemporal and quantitative evaluation of altered AH dynamics and ocular tissue permeability for better understanding the physiological mechanisms of ocular hypertension and the efficacy of antiglaucoma drug treatments.
Gadolinium-enhanced MRI allows spatiotemporal and quantitative evaluation of altered aqueous humor dynamics and ocular tissue permeability upon chronic ocular hypertension and pharmacologic interventions. It also reveals the systemic effects of topical hypotensive drugs during glaucoma treatment.
PMCID: PMC4062398  PMID: 24764067
gadolinium; magnetic resonance imaging; aqueous humor dynamics; ocular tissue permeability; intraocular pressure
2.  OCT for glaucoma diagnosis, screening and detection of glaucoma progression 
The British Journal of Ophthalmology  2013;98(Suppl 2):ii15-ii19.
Optical coherence tomography (OCT) is a commonly used imaging modality in the evaluation of glaucomatous damage. The commercially available spectral domain (SD)-OCT offers benefits in glaucoma assessment over the earlier generation of time domain-OCT due to increased axial resolution, faster scanning speeds and has been reported to have improved reproducibility but similar diagnostic accuracy. The capabilities of SD-OCT are rapidly advancing with 3D imaging, reproducible registration, and advanced segmentation algorithms of macular and optic nerve head regions. A review of the evidence to date suggests that retinal nerve fibre layer remains the dominant parameter for glaucoma diagnosis and detection of progression while initial studies of macular and optic nerve head parameters have shown promising results. SD-OCT still currently lacks the diagnostic performance for glaucoma screening.
PMCID: PMC4208340  PMID: 24357497
3.  Characterisation of Schlemm's canal cross-sectional area 
The British Journal of Ophthalmology  2014;98(Suppl 2):ii10-ii14.
To compare three methods of Schlemm's canal (SC) cross-sectional area (CSA) measurement.
Ten eyes (10 healthy volunteers) were imaged three times using spectral-domain optical coherence tomography (Cirrus HD-OCT, Zeiss, Dublin, California, USA). Aqueous outflow vascular structures and SC collector channel ostia were used as landmarks to identify a reference location within the limbus. SC CSA was assessed within a 1 mm segment (±15 frames of the reference, 31 frames in all) by three techniques. (1) Using a random number table, SC CSA in five random frames from the set of 31 surrounding the reference were measured and averaged. (2) The most easily visualised SC location (subjective) was measured, and (3) SC CSA was measured in all 31 consecutive B-scans, and averaged. (comprehensive average, gold standard). Subjective and random CSAs were compared with the comprehensive by general estimating equation modelling, and structural equation modelling quantified agreement.
The average from five random locations (4175±1045 µm2) was not significantly different than that obtained from the gold standard comprehensive assessment (4064±1308 µm2, p=0.6537). Subjectively located SC CSA (7614±2162 µm2) was significantly larger than the comprehensive gold standard SC CSA (p<0.0001). The average of five random frames produced significantly less bias than did subjective location, yielding a calibration line crossing the ‘no-bias’ line.
Subjectively located SC CSA measurements produce high estimates of SC CSA. SC assessed by measuring five random locations estimate CSA was similar to the gold standard estimate.
PMCID: PMC4208345  PMID: 24590558
Aqueous humour; Imaging
4.  A Laser-Induced Mouse Model with Long-Term Intraocular Pressure Elevation 
PLoS ONE  2014;9(9):e107446.
To develop and characterize a mouse model with intraocular pressure (IOP) elevation after laser photocoagulation on the trabecular meshwork (TM), which may serve as a model to investigate the potential of stem cell-based therapies for glaucoma.
IOP was measured in 281 adult C57BL/6 mice to determine normal IOP range. IOP elevation was induced unilaterally in 50 adult mice, by targeting the TM through the limbus with a 532-nm diode laser. IOP was measured up to 24 weeks post-treatment. The optic nerve damage was detected by electroretinography and assessed by semiautomatic counting of optic nerve axons. Effects of laser treatment on the TM were evaluated by histology, immunofluorescence staining, optical coherence tomography (OCT) and transmission electron microscopy (TEM).
The average IOP of C57BL/6 mice was 14.5±2.6 mmHg (Mean ±SD). After laser treatment, IOP averaged above 20 mmHg throughout the follow-up period of 24 weeks. At 24 weeks, 57% of treated eyes had elevated IOP with the mean IOP of 22.5±2.5 mmHg (Mean ±SED). The difference of average axon count (59.0%) between laser treated and untreated eyes was statistically significant. Photopic negative response (PhNR) by electroretinography was significantly decreased. CD45+ inflammatory cells invaded the TM within 1 week. The expression of SPARC was increased in the TM from 1 to 12 weeks. Histology showed the anterior chamber angle open after laser treatment. OCT indicated that most of the eyes with laser treatment had no synechia in the anterior chamber angles. TEM demonstrated disorganized and compacted extracellular matrix in the TM.
An experimental murine ocular hypertension model with an open angle and optic nerve axon loss was produced with laser photocoagulation, which could be used to investigate stem cell-based therapies for restoration of the outflow pathway integrity for ocular hypertension or glaucoma.
PMCID: PMC4162591  PMID: 25216052
5.  The NEIGHBOR Consortium Primary Open Angle Glaucoma Genome-wide Association Study: Rationale, Study design and Clinical variables 
Journal of glaucoma  2013;22(7):517-525.
Primary open-angle glaucoma (POAG) is a common disease with complex inheritance. The identification of genes predisposing to POAG is an important step toward the development of novel gene-based methods of diagnosis and treatment. Genome-wide association studies (GWAS) have successfully identified genes contributing to complex traits such as POAG however, such studies frequently require very large sample sizes, and thus, collaborations and consortia have been of critical importance for the GWAS approach. In this report we describe the formation of the NEIGHBOR consortium, the harmonized case control definitions used for a POAG GWAS, the clinical features of the cases and controls and the rationale for the GWAS study design.
PMCID: PMC3485429  PMID: 22828004
6.  IOP Elevation Reduces Schlemm's Canal Cross-Sectional Area 
Previously, we demonstrated reduced Schlemm's canal cross-sectional area (SC-CSA) with increased perfusion pressure in a cadaveric flow model. The purpose of the present study was to determine the effect of acute IOP elevation on SC-CSA in living human eyes.
The temporal limbus of 27 eyes of 14 healthy subjects (10 male, 4 female, age 36 ± 13 years) was imaged by spectral-domain optical coherence tomography at baseline and with IOP elevation (ophthalmodynamometer set at 30-g force). Intraocular pressure was measured at baseline and with IOP elevation by Goldmann applanation tonometry. Vascular landmarks were used to identify corresponding locations in baseline and IOP elevation scan volumes. Schlemm's canal CSA at five locations within a 1-mm length of SC was measured in ImageJ as described previously. A linear mixed-effects model quantified the effect of IOP elevation on SC-CSA.
The mean IOP increase was 189%, and the mean SC-CSA decrease was 32% (P < 0.001). The estimate (95% confidence interval) for SC-CSA response to IOP change was −66.6 (−80.6 to −52.7) μm2/mm Hg.
Acute IOP elevation significantly reduces SC-CSA in healthy eyes. Acute dynamic response to IOP elevation may be a useful future characterization of ocular health in the management of glaucoma.
Visualization of a stress strain response in the aqueous humor outflow tract is presented. Using an ophthalmodynamometer to create an acute IOP increase in normal healthy eyes, morphometric changes in Schlemm's canal can be observed and quantified in OCT imagery.
PMCID: PMC3968930  PMID: 24526436
ophthalmodynamometer; optical coherence tomography; outflow tract imaging
7.  There has to be a better way evolution of internal filtration glaucoma surgeries 
The British journal of ophthalmology  2013;97(10):1228-1229.
PMCID: PMC4122115  PMID: 24049122
8.  Outflow Tract Ablation Using a Conditionally Cytotoxic Feline Immunodeficiency Viral Vector 
To create an in vivo model of vector-mediated trabecular meshwork (TM) ablation and replacement.
We generated a conditionally cytotoxic, trackable vector, HSVtkiG, that expressed herpes simplex virus 1 thymidine kinase (HSVtk) and enhanced green fluorescent protein (eGFP). We optimized HSVtkiG ablation in vitro with ganciclovir (GCV) in comparison to eGFP control vector GINSIN and investigated the mechanism. Right eyes of 24 rats were then injected intracamerally with either HSVtkiG or GINSIN, before intraperitoneal GCV was administered 1 week later. Intraocular pressure, central corneal thickness (CCT), and slit-lamp exams were assessed for 8 weeks. Transduction and ablation were followed by gonioscopic visualization of eGFP. Histology was obtained with TM cell counts and immunohistochemistry markers of inflammation.
Transduction and ablation parameters were established in vitro. Apoptosis was the cause of cell death. In vivo, transduction was seen gonioscopically to be targeted to the TM, followed by disappearance of eGFP marker fluorescence in HSVtkiG-transduced cells after injection of GCV. Ablation resulted in an IOP decrease of 25% in HSVtkiG-injected eyes 2 days after GCV but not in GINSIN or noninjected control eyes (P < 0.05). Trabecular meshwork cellularity was decreased at the time of lowest IOP and recovered thereafter, while CCT remained unchanged. Inflammation was absent.
A vector-based system for inducible ablation of cells of the outflow tract was developed. Trabecular meshwork ablation lowered IOP, and recovery of cellularity and IOP followed. This model may be useful to study pressure regulation by the TM, its stem cells, and migration patterns.
We used an in vivo trackable, conditionally cytotoxic feline immunodeficiency viral (FIV) vector with an HSVtk cassette to ablate the trabecular meshwork in the rat. Ablation lowered IOP, and recovery of cellularity followed. This model may be useful to study pressure regulation by the TM, its stem cells, and migration patterns.
PMCID: PMC3929079  PMID: 24448264
glaucoma; trabecular meshwork; gene therapy; ablation
9.  Quantitative 3D-OCT motion correction with tilt and illumination correction, robust similarity measure and regularization 
Biomedical Optics Express  2014;5(8):2591-2613.
Variability in illumination, signal quality, tilt and the amount of motion pose challenges for post-processing based 3D-OCT motion correction algorithms. We present an advanced 3D-OCT motion correction algorithm using image registration and orthogonal raster scan patterns aimed at addressing these challenges. An intensity similarity measure using the pseudo Huber norm and a regularization scheme based on a pseudo L0.5 norm are introduced. A two-stage registration approach was developed. In the first stage, only axial motion and axial tilt are coarsely corrected. This result is then used as the starting point for a second stage full optimization. In preprocessing, a bias field estimation based approach to correct illumination differences in the input volumes is employed. Quantitative evaluation was performed using a large set of data acquired from 73 healthy and glaucomatous eyes using SD-OCT systems. OCT volumes of both the optic nerve head and the macula region acquired with three independent orthogonal volume pairs for each location were used to assess reproducibility. The advanced motion correction algorithm using the techniques presented in this paper was compared to a basic algorithm corresponding to an earlier version and to performing no motion correction. Errors in segmentation-based measures such as layer positions, retinal and nerve fiber thickness, as well as the blood vessel pattern were evaluated. The quantitative results consistently show that reproducibility is improved considerably by using the advanced algorithm, which also significantly outperforms the basic algorithm. The mean of the mean absolute retinal thickness difference over all data was 9.9 um without motion correction, 7.1 um using the basic algorithm and 5.0 um using the advanced algorithm. Similarly, the blood vessel likelihood map error is reduced to 69% of the uncorrected error for the basic and to 47% of the uncorrected error for the advanced algorithm. These results demonstrate that our advanced motion correction algorithm has the potential to improve the reliability of quantitative measurements derived from 3D-OCT data substantially.
PMCID: PMC4132991  PMID: 25136488
(170.4500) Optical coherence tomography; (170.4470) Ophthalmology; (100.2980) Image enhancement; (100.5010) Pattern recognition
10.  In Vivo Lamina Cribrosa Micro-Architecture in Healthy and Glaucomatous Eyes as Assessed by Optical Coherence Tomography 
The lamina cribrosa (LC) is a prime location of glaucomatous damage. The purpose of this study was to compare LC 3-dimensional micro-architecture between healthy and glaucomatous eyes in vivo by using optical coherence tomography (OCT).
Sixty-eight eyes (19 healthy and 49 glaucomatous) from 47 subjects were scanned in a 3.5 × 3.5 × 3.64-mm volume (400 × 400 × 896 pixels) at the optic nerve head by using swept-source OCT. The LC micro-architecture parameters were measured on the visible LC by an automated segmentation algorithm. The LC parameters were compared to diagnosis and visual field mean deviation (VF MD) by using a linear mixed effects model accounting for age.
The average VF MD for the healthy and glaucomatous eyes was −0.50 ± 0.80 dB and −7.84 ± 8.75 dB, respectively. Beam thickness to pore diameter ratio (P = 0.04) and pore diameter standard deviation (P < 0.01) were increased in glaucomatous eyes. With worse MD, beam thickness to pore diameter ratio (P < 0.01), pore diameter standard deviation (P = 0.05), and beam thickness (P < 0.01) showed a statistically significant increase while pore diameter (P = 0.02) showed a significant decrease. There were no significant interactions between any of the parameters and age (all P > 0.05).
Glaucomatous micro-architecture changes in the LC, detected by OCT analysis, reflect beams remodeling and axonal loss leading to reduction in pore size and increased pore size variability.
Using swept-source OCT we demonstrated in vivo significant differences in the lamina cribrosa micro-architecture between healthy and glaucomatous eyes. These changes reflect beams remodeling and axonal loss leading to reduction in pore size and increased pore size variability.
PMCID: PMC3869422  PMID: 24302585
lamina cribrosa; optical coherence tomography; glaucoma
11.  Reproducibility of In-Vivo OCT Measured Three-Dimensional Human Lamina Cribrosa Microarchitecture 
PLoS ONE  2014;9(4):e95526.
To determine the reproducibility of automated segmentation of the three-dimensional (3D) lamina cribrosa (LC) microarchitecture scanned in-vivo using optical coherence tomography (OCT).
Thirty-nine eyes (8 healthy, 19 glaucoma suspects and 12 glaucoma) from 49 subjects were scanned twice using swept-source (SS−) OCT in a 3.5×3.5×3.64 mm (400×400×896 pixels) volume centered on the optic nerve head, with the focus readjusted after each scan. The LC was automatically segmented and analyzed for microarchitectural parameters, including pore diameter, pore diameter standard deviation (SD), pore aspect ratio, pore area, beam thickness, beam thickness SD, and beam thickness to pore diameter ratio. Reproducibility of the parameters was assessed by computing the imprecision of the parameters between the scans.
The automated segmentation demonstrated excellent reproducibility. All LC microarchitecture parameters had an imprecision of less or equal to 4.2%. There was little variability in imprecision with respect to diagnostic category, although the method tends to show higher imprecision amongst healthy subjects.
The proposed automated segmentation of the LC demonstrated high reproducibility for 3D LC parameters. This segmentation analysis tool will be useful for in-vivo studies of the LC.
PMCID: PMC3991692  PMID: 24747957
12.  Repeatability of in vivo 3D lamina cribrosa microarchitecture using adaptive optics spectral domain optical coherence tomography 
Biomedical Optics Express  2014;5(4):1114-1123.
We demonstrate the repeatability of lamina cribrosa (LC) microarchitecture for in vivo 3D optical coherence tomography (OCT) scans of healthy, glaucoma suspects, and glaucomatous eyes. Eyes underwent two scans using a prototype adaptive optics spectral domain OCT (AO-SDOCT) device from which LC microarchitecture was semi-automatically segmented. LC segmentations were used to quantify pore and beam structure through several global microarchitecture parameters. Repeatability of LC microarchitecture was assessed qualitatively and quantitatively by calculating parameter imprecision. For all but one parameters (pore volume) measurement imprecision was <4.7% of the mean value, indicating good measurement reproducibility. Imprecision ranged between 27.3% and 54.5% of the population standard deviation for each parameter, while there was not a significant effect on imprecision due to disease status, indicating utility in testing for LC structural trends.
PMCID: PMC3986004  PMID: 24761293
(100.2000) Digital image processing; (170.4470) Ophthalmology; (110.4500) Optical coherence tomography; (170.1610) Clinical applications; (330.4460) Ophthalmic optics and devices
13.  Gold Nanorods as a Contrast Agent for Doppler Optical Coherence Tomography 
PLoS ONE  2014;9(3):e90690.
To investigate gold nanorods (GNRs) as a contrast agent to enhance Doppler optical coherence tomography (OCT) imaging of the intrascleral aqueous humor outflow.
A serial dilution of GNRs was scanned with a spectral-domain OCT device (Bioptigen, Durham, NC) to visualize Doppler signal. Doppler measurements using GNRs were validated using a controlled flow system. To demonstrate an application of GNR enhanced Doppler, porcine eyes were perfused at constant pressure with mock aqueous alone or 1.0×1012 GNR/mL mixed with mock aqueous. Twelve Doppler and volumetric SD-OCT scans were obtained from the limbus in a radial fashion incremented by 30°, forming a circular scan pattern. Volumetric flow was computed by integrating flow inside non-connected vessels throughout all 12 scans around the limbus.
At the GNR concentration of 0.7×1012 GNRs/mL, Doppler signal was present through the entire depth of the testing tube without substantial attenuation. A well-defined laminar flow profile was observed for Doppler images of GNRs flowing through the glass capillary tube. The Doppler OCT measured flow profile was not statistically different from the expected flow profile based upon an autoregressive moving average model, with an error of −0.025 to 0.037 mm/s (p = 0.6435). Cross-sectional slices demonstrated the ability to view anterior chamber outflow ex-vivo using GNR-enhanced Doppler OCT. Doppler volumetric flow measurements were comparable to flow recorded by the perfusion system.
GNRs created a measureable Doppler signal within otherwise silent flow fields in OCT Doppler scans. Practical application of this technique was confirmed in a constant pressure ex-vivo aqueous humor outflow model in porcine eyes.
PMCID: PMC3940929  PMID: 24595044
14.  CDKN2B-AS1 Genotype – Glaucoma Feature Correlations in Primary Open-Angle Glaucoma Patients from the United States 
American journal of ophthalmology  2012;155(2):342-353.e5.
To assess the association between single nucleotide polymorphisms (SNPs) of the gene region containing cyclin dependent kinase inhibitor 2B antisense noncoding RNA (CDKN2B-AS1) and glaucoma features among primary open-angle glaucoma (POAG) patients.
Retrospective observational case series.
We studied associations between ten CDKN2B-AS1 SNPs and glaucoma features among 976 POAG cases from the Glaucoma Genes and Environment (GLAUGEN) study and 1971 cases from the National Eye Institute Glaucoma Human Genetics Collaboration (NEIGHBOR) consortium. For each patient, we chose the feature from the eye with the higher value. We created cohort-specific multivariable models for glaucoma features and then meta-analyzed the results.
For nine of the ten protective CDKN2B-AS1 SNPs with minor alleles associated with reduced disease risk (e.g., the G allele at rs2157719), POAG patients carrying these minor alleles had smaller cup-disc ratio (0.05 units smaller per G allele at diagnosis; 95% CI: −0.08, −0.03; p=6.23E-05) despite having higher intraocular pressure (IOP) (0.70 mm Hg higher per G allele at DNA collection; 95% CI: 0.40, 1.00; P=5.45E-06). For the one adverse rs3217992 SNP with minor allele A associated with increased disease risk, POAG patients with A alleles had larger cup-disc ratio (0.05 units larger per A allele at diagnosis; 95% CI: 0.02, 0.07; P=4.74E-04) despite having lower IOP (−0.57 mm Hg per A allele at DNA collection; 95% CI: −0.84, −0.29; P=6.55E-05).
Alleles of CDKN2B-AS1 SNPs, which influence risk of developing POAG, also modulate optic nerve degeneration among POAG patients, underscoring the role of CDKN2B-AS1 in POAG.
PMCID: PMC3544983  PMID: 23111177
15.  Retinal Nerve Fiber Layer Atrophy Is Associated with Visual Field Loss over Time in Glaucoma Suspect and Glaucomatous Eyes 
American journal of ophthalmology  2012;155(1):73-82.e1.
To prospectively compare detection of progressive retinal nerve fiber layer thickness (RNFL) atrophy identified using time-domain optical coherence tomography (OCT) with visual field progression using standard automated perimetry (SAP) in glaucoma suspect and preperimetric glaucoma and perimetric glaucoma patients.
Prospective longitudinal clinical trial
Eligible eyes with ≥2 years of follow-up underwent time-domain OCT and SAP every 6 months. The occurrence of visual field progression was defined as the first follow-up visit reaching a significant (p<0.05) negative visual field index (VFI) slope over time. RNFL progression/improvement was defined as a significant negative/positive slope over time. Specificity was defined as the number of eyes with neither progression nor improvement, divided by the number of eyes without progression. Cox proportional hazard ratios (HR) were calculated using univariate and multivariate models with RNFL loss as a time-dependent covariate.
310 glaucoma suspect and preperimetric glaucoma, and 177 perimetric glaucoma eyes were included. Eighty-nine eyes showed visual field progression and 101 eyes showed RNFL progression. The average time to detect visual field progression in those 89 eyes was 35±13 months; and to detect RNFL progression in those 101 eyes was 36±13 months. In multivariate Cox models, average and superior RNFL losses were associated with subsequent VFI loss in the entire cohort (every 10μm loss, HR=1.38,p=0.03; HR=1.20, p=0.01 respectively). Among the entire cohort of 487 eyes, 42 had significant VFI improvement and 55 had significant RNFL improvement (specificity 91.4% and 88.7%, respectively).
Structural progression is associated with functional progression in glaucoma suspect and glaucomatous eyes. Average and superior RNFL thickness may predict subsequent SAP loss.
PMCID: PMC3525739  PMID: 23036570
retinal nerve fiber layer; visual field; glaucoma progression; hazard ratio
16.  Individual A-Scan Signal Normalization Between Two Spectral Domain Optical Coherence Tomography Devices 
We developed a method to normalize optical coherence tomography (OCT) signal profiles from two spectral-domain (SD) OCT devices so that the comparability between devices increases.
We scanned 21 eyes from 14 healthy and 7 glaucoma subjects with two SD-OCT devices on the same day, with equivalent cube scan patterns centered on the fovea (Cirrus HD-OCT and RTVue). Foveola positions were selected manually and used as the center for registration of the corresponding images. A-scan signals were sampled 1.8 mm from the foveola in the temporal, superior, nasal, and inferior quadrants. After oversampling and rescaling RTVue data along the Z-axis to match the corresponding Cirrus data format, speckle noise reduction and amplitude normalization were applied. For comparison between normalized A-scan profiles, mean absolute difference in amplitude in percentage was measured at each sampling point. As a reference, the mean absolute difference between two Cirrus scans on the same eye also was measured.
The mean residual of the A-scan profile amplitude was reduced significantly after signal normalization (12.7% vs. 6.2%, P < 0.0001, paired t-test). All four quadrants also showed statistically significant reduction (all P < 0.0001). Mean absolute difference after normalization was smaller than the one between two Cirrus scans. No performance difference was detected between health and glaucomatous eyes.
The reported signal normalization method successfully reduced the A-scan profile differences between two SD-OCT devices. This signal normalization processing may improve the direct comparability of OCT image analysis and measurement on various devices.
A novel signal normalization method for SD-OCT images was developed and tested to improve the direct comparability of image analysis and clinical measurements between devices. The A-scan profile differences between 2 SD-OCT devices were reduced significantly after normalization.
PMCID: PMC3658265  PMID: 23611992
optical coherence tomography; image analysis; comparability
17.  Automated lamina cribrosa microstructural segmentation in optical coherence tomography scans of healthy and glaucomatous eyes 
Biomedical Optics Express  2013;4(11):2596-2608.
We demonstrate an automated segmentation method for in-vivo 3D optical coherence tomography (OCT) imaging of the lamina cribrosa (LC). Manual segmentations of coronal slices of the LC were used as a gold standard in parameter selection and evaluation of the automated technique. The method was validated using two prototype OCT devices; each had a subject cohort including both healthy and glaucomatous eyes. Automated segmentation of in-vivo 3D LC OCT microstructure performed comparably to manual segmentation and is useful for investigative research and in clinical quantification of the LC.
PMCID: PMC3829553  PMID: 24298418
(100.2000) Digital image processing; (170.4470) Ophthalmology; (110.4500) Optical coherence tomography; (170.1610) Clinical applications; (330.4460) Ophthalmic optics and devices
18.  Optic Nerve Head and Retinal Nerve Fiber Layer Analysis 
Ophthalmology  2007;114(10):1937-1949.
To evaluate the current published literature on the use of optic nerve head (ONH) and retinal nerve fiber layer (RNFL) measurement devices in diagnosing open-angle glaucoma and detecting progression.
A search of peer-reviewed literature was conducted on February 15, 2006 in PubMed and the Cochrane Library for the period January 2003 to February 2006. The search was limited to studies of adults in English-language journals and yielded 442 citations. The panel reviewed the abstracts of these articles and selected 159 articles of possible clinical relevance for review. Of these 159 full-text articles, 82 were determined to be relevant for the first author and methodologist to review and rate according to the quality of evidence.
There were no studies classified as having the highest level of evidence (level I). The ONH and RNFL imaging instruments reviewed in this assessment were determined to be highly effective in distinguishing eyes with glaucomatous visual field (VF) loss from normal eyes without VF loss, based on level II evidence. In addition, some studies demonstrated that parameters from ONH or RNFL imaging predicted the development of VF defects among glaucoma suspects. Studies on detecting glaucoma progression showed that although there was often agreement on progression between the structural and functional (VF) tests, a significant proportion of glaucoma patients progressed by either the structural or the functional test alone.
The ONH and RNFL imaging devices provide quantitative information for the clinician. Based on studies that have compared the various available technologies directly, there is no single imaging device that outperforms the others in distinguishing patients with glaucoma from controls. Ongoing advances in imaging and related software, as well as the impracticalities associated with obtaining and assessing optic nerve stereophotographs, have made imaging increasingly important in many practice settings. The information obtained from imaging devices is useful in clinical practice when analyzed in conjunction with other relevant parameters that define glaucoma diagnosis and progression.
PMCID: PMC3780976  PMID: 17908595
19.  Advanced scanning methods with tracking optical coherence tomography 
Optics express  2005;13(20):7937-7947.
An upgraded optical coherence tomography system with integrated retinal tracker (TOCT) was developed. The upgraded system uses improved components to extend the tracking bandwidth, fully integrates the tracking hardware into the optical head of the clinical OCT system, and operates from a single software platform. The system was able to achieve transverse scan registration with sub-pixel accuracy (~10 μm). We demonstrate several advanced scan sequences with the TOCT, including composite scans averaged (co-added) from multiple B-scans taken consecutively and several hours apart, en face images collected by summing the A-scans of circular, line, and raster scans, and three-dimensional (3D) retinal maps of the fovea and optic disc. The new system achieves highly accurate OCT scan registration yielding composite images with significantly improved spatial resolution, increased signal-to-noise ratio, and reduced speckle while maintaining well-defined boundaries and sharp fine structure compared to single scans. Precise re-registration of multiple scans over separate imaging sessions demonstrates TOCT utility for longitudinal studies. En face images and 3D data cubes generated from these data reveal high fidelity image registration with tracking, despite scan durations of more than one minute.
PMCID: PMC3763241  PMID: 19498823
20.  Evaluating Objective and Subjective Quantitative Parameters at the Initial Visit to Predict Future Glaucomatous Visual Field Progression 
To evaluate the ability of structural assessment to predict glaucomatous visual field progression.
A total of 119 healthy eyes with suspected glaucoma and glaucomatous eyes with 5 or more optic nerve stereophotographs, optical coherence tomography (OCT), and confocal scanning laser ophthalmoscopy (CSLO) all acquired within 6 months of each other were enrolled. Odds ratios to predict progression were determined by generalized estimating equation models.
Median follow-up was 4.0 years (range: 1.5 to 5.7 years). Fifteen eyes progressed by glaucoma progression analysis, 20 by visual field index, and 10 by both. Baseline parameters from stereophotographs (vertical cup-to-disc ratio and Disc Damage Likelihood Scale), OCT (global, superior quadrant, and inferior quadrant retinal nerve fiber layer thickness), and CSLO (cup shape measure and mean cup depth) were significant predictors of progression. Comparing the single best parameter from all models, only the OCT superior quadrant RNFL predicted progression.
Baseline stereophotographs, OCT, and CSLO measurements may be clinically useful to predict glaucomatous visual field progression.
PMCID: PMC3444548  PMID: 22658308
21.  Visualization of the Conventional Outflow Pathway in the Living Human Eye 
Ophthalmology  2012;119(8):1563-1568.
The purpose of this study was to visualize the aqueous outflow system in three dimensions (3D) in living human eyes, and to investigate the use of commercially available Spectral-domain optical coherence tomographic (SD-OCT) systems for this purpose.
This was a prospective observational study.
Participants and/or Controls
One randomly determined eye in each of six normal healthy subjects was included.
3D SD-OCT imaging of the aqueous humor outflow structures was performed with two devices: Cirrus HD-OCT (Carl Zeiss Meditec, Inc., Dublin CA) and Bioptigen SDOIS (Bioptigen, Inc., Research Triangle, NC).
Main Outcome Measures
3D virtual castings of Schlemm’s canal (SC) and more distal outflow structures created from scan data from each device.
Virtual casting of SC provided visualization of more aqueous vessels branching from SC than could be located by interrogating the 2D image stack. Similarly, virtual casting of distal structures allowed visualization of large and small aqueous outflow channel networks that could not be appreciated with the conventional 2D visualization.
The outflow pathways from SC to the superficial vasculature can be identified and tracked in living human eyes using commercially available SD-OCT.
PMCID: PMC3411861  PMID: 22683063
22.  Glaucoma Discrimination of Segmented Cirrus Spectral Domain Optical Coherence Tomography (SD-OCT) Macular Scans 
The British journal of ophthalmology  2012;96(11):1420-1425.
To evaluate the glaucoma discriminating ability of macular retinal layers as measured by spectral-domain optical coherence tomography (SD-OCT).
Healthy, glaucoma suspect and glaucomatous subjects had a comprehensive ocular examination, visual field testing and SD-OCT imaging (Cirrus HD-OCT; Carl Zeiss Meditec, Dublin, CA) in the macular and optic nerve head regions. OCT macular scans were segmented into macular nerve fiber layer (mNFL), ganglion cell layer with inner plexiform layer (GCIP), ganglion cell complex (GCC) (composed of mNFL and GCIP), outer retinal complex (ORC) and total retina (TR). Glaucoma discriminating ability was assessed using the area under the receiver operator characteristic curve (AUC) for all macular parameters and mean circumpapillary (cp) RNFL. Glaucoma suspects and glaucoma subjects were grouped together for the calculation of AUCs.
Analysis was performed on 51 healthy, 49 glaucoma suspect and 63 glaucomatous eyes. The median visual field MD was −2.21dB (interquartile range (IQR): −6.92 to −0.35) for the glaucoma group, −0.32dB (IQR: −1.22 to 0.73) for the suspect group and −0.18dB (IQR: −0.92 to 0.71) for the healthy group. Highest age adjusted AUCs for discriminating between healthy and glaucomatous eyes were found for average GCC and GCIP (AUC=0.901 and 0.900, respectively), and their sectoral measurements: infero-temporal (0.922 and 0.913), inferior (0.904 and 0.912) and supero-temporal (0.910 and 0.897). These values were similar to the discriminating ability of the mean cpRNFL (AUC=0.913). Comparison of these AUCs did not yield any statistically significant difference (all p>0.05). Similar discrimination performance but with slight reduction in AUCs was achieved for comparison between healthy and the combination of glaucoma and glaucoma suspect eyes.
SD-OCT GCIP and GCC measurements showed similar glaucoma diagnostic ability and was comparable with that of cpRNFL.
PMCID: PMC3721629  PMID: 22914498
23.  Detection of Glaucoma Progression by Population and Individual Derived Variability Criteria 
Ocular imaging devices provide quantitative structural information that might improve glaucoma progression detection. This study examined scanning laser polarimetry (SLP) population-derived versus individual-derived cut-off criteria for detecting progression.
Forty-eight healthy, glaucoma suspect and glaucoma subjects, providing 76 eyes were used. All subjects had reliable visual field (VF) and SLP scans acquired at the same visits from ≥ 4 visits. VF progression was defined by guided progression analysis (GPA) and by the VF index (VFI). SLP measurements were analyzed by fast mode (FM) GPA, compared to the population rate of progression, and extended mode (EM) GPA, compared to the individual variability. The agreement between progression detection methods was measured.
Poor agreement was observed between progression defined by VF and FM and EM. The difference in TSNIT average rate of change between VF defined progressors and non-progressors for both FM (p=0.010) and EM (p=0.015) was statistically significant.
There is poor agreement between VF and SLP progression regardless of the use of population derived or individual variability criteria. The best SLP progression detection method could not be ascertained, therefore, acquiring three SLP scans per visit is recommended.
PMCID: PMC3721630  PMID: 23203702
Scanning laser polarimetry; glaucoma progression
24.  Automated Foveola Localization in Retinal 3D-OCT Images Using Structural Support Vector Machine Prediction 
We develop an automated method to determine the foveola location in macular 3D-OCT images in either healthy or pathological conditions. Structural Support Vector Machine (S-SVM) is trained to directly predict the location of the foveola, such that the score at the ground truth position is higher than that at any other position by a margin scaling with the associated localization loss. This S-SVM formulation directly minimizes the empirical risk of localization error, and makes efficient use of all available training data. It deals with the localization problem in a more principled way compared to the conventional binary classifier learning that uses zero-one loss and random sampling of negative examples. A total of 170 scans were collected for the experiment. Our method localized 95.1% of testing scans within the anatomical area of the foveola. Our experimental results show that the proposed method can effectively identify the location of the foveola, facilitating diagnosis around this important landmark.
PMCID: PMC3717593  PMID: 23285565
25.  Macula assessment using optical coherence tomography for glaucoma diagnosis 
The British journal of ophthalmology  2012;96(12):1452-1455.
Optical coherence tomography (OCT) is an interferometry-based imaging modality that generates high-resolution cross-sectional images of the retina. Circumpapillary retinal nerve fiber layer (cpRNFL) and optic nerve head assessments are the mainstay of glaucomatous structural measurements in OCT. However, because these measurements are not always available or precise, it would be useful to have another reliable indicator. The macula has been suggested as an alternative scanning location for glaucoma diagnosis. Using time-domain (TD-) OCT, macular measurements have shown to provide good glaucoma diagnostic capabilities. With the adoption of spectral-domain OCT, which allows a higher image resolution than TD-OCT, segmentation of inner macular layers becomes possible. These layers are specifically prone to glaucomatous damage and thickness measurements show a comparable performance to that of glaucomatous cpRNFL measurements. The role of macular measurements for detection of glaucoma progression is still under investigation. More sophisticated measurement and analysis tools that can amplify the advantages of macular measurements are expected. For example, improvement of image quality would allow better visualization, development of various scanning modes would optimize macular measurements, and further refining of the analytical algorithm would provide more accurate segmentation. With these achievements, macular measurement can be an important surrogate for glaucomatous structural assessment.
PMCID: PMC3718015  PMID: 23018425

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